U.S. Pat. No. 5,100,889 to Misra et al discloses 7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogs which are thromboxane A.sub.2 (TXA.sub.2) receptor antagonists or combined thromboxane A.sub.2 receptor antagonist/thromboxane synthetase inhibitors useful, for example, in the treatment of thrombotic and/or vasospastic diseases, and have good duration of action. Examples of compounds disclosed in Misra et al have the structural formula ##STR3## and including all stereoisomers thereof, wherein m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;
R.sup.1 is hydrogen, lower alkyl, aralkyl, aryl, cycloalkyl, cycloalkylalkyl, or amide ##STR4## wherein t is 1 to 12 and R.sub.a is lower alkyl, aryl, cycloalkyl, or cycloalkylalkyl); PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring. PA1 R.sup.9 is H, OH or lower alkyl, which includes the steps of PA1 (b) treating the amine with a silylating agent and maleic anhydride to form silylated compound of the structure ##STR24## and (c) treating the silylated compound with water, a desilylating agent, a cyclizing agent, and an organic base to form the maleimide intermediate. PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or PA1 R.sup.1 and R.sup.2 together with the N to which they are linked form a 5- to 8-membered ring which contains only the single N heteroatom; PA1 or esters thereof or pharmaceutically acceptable salts thereof, which includes the steps of forming a maleimide intermediate of the structure ##STR30## (employing the methods of preparation as described above), reacting the above imide with furan in the presence of a Lewis acid to form an imide of the structure ##STR31## reducing the imide VI by reacting the imide VI with hydrogen in the presence of a reduction catalyst to form the imide intermediate ##STR32## and employing the imide intermediate VII to form the oxazole acid, ester thereof or pharmaceutically acceptable salt thereof. PA1 R.sup.8 is H, aryl or lower alkyl and PA1 R.sup.9 is H, OH or lower alkyl. PA1 R.sup.2 is hydrogen, lower alkyl, aryl, or aralkyl; or R.sup.1 and R.sup.2 together with the nitrogen to which they are linked may form a 5- to 8-membered ring. PA1 R.sup.1 is preferably lower alkyl such as n-pentyl, aryl such as phenyl, halophenyl such as 4-chlorophenyl, or cyclohexylalkyl, such as cyclohexylbutyl. PA1 R.sup.2 is preferably H or phenyl. ##STR50##
Misra et al disclose that these compounds may be prepared by transmetallating bromophenylalkyl A ##STR5## by treatment with t-C.sub.4 H.sub.9 Li or n-C.sub.4 H.sub.9 Li or subjecting A to a Grignard reaction by treatment with Mg, and then condensing with perhydrobenzofuran-1-ol B ##STR6## to form the condensed 7-oxabicycloheptane alcohol compound of the structure C ##STR7## and then subjecting the condensed compound to hydrogenolysis to form the following alcohol ##STR8## Where Pro is thexyldimethylsilyl or t-butyldimethylsilyl, the alcohol is acetylated and the silyl protecting group of the so-formed acetate is removed to form the following acetate: ##STR9## which is treated with a protecting compound and the acetate is removed by treatment with aqueous hydroxide or excess methyllithium to form the following alcohol: ##STR10## (where Pro is t-butyldiphenylsilyl).
The protected alcohol is subjected to a Jones oxidation to form the following acid: ##STR11##
The so-formed carboxylic acid intermediate is then employed to make the final compound.
In a more preferred procedure, Misra et al disclose protecting the alcohol function of alcohol C to form the protected alcohol ##STR12## subjecting the protected alcohol H to a Jones oxidation and esterification to form the ester ##STR13## which is made to undergo hydrogenolysis and subsequent removal of the acetate protecting group by transesterification to afford the alcohol ##STR14## which is subjected to a Jones oxidation to form the carboxylic acid intermediate L ##STR15##
In an alternative procedure where n is 1, the above carboxylic acid intermediate L is formed by treating F (n=2) with acetic anhydride and removing the protecting group to form the acetate alcohol ##STR16## which is made to undergo a Dess-Martin oxidation to form the aldehyde ##STR17## The above aldehyde is oxidized and esterified to the corresponding acetate ester, deprotected, and subjected to a Jones oxidation to form carboxylic acid L where n is 1.